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1
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Oleszycka E, Kwiecień K, Grygier B, Cichy J, Kwiecińska P. The many faces of DGAT1. Life Sci 2025; 362:123322. [PMID: 39709166 DOI: 10.1016/j.lfs.2024.123322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/11/2024] [Accepted: 12/18/2024] [Indexed: 12/23/2024]
Abstract
Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is a multifaced enzyme with a wide spectrum of substrates, from lipids through waxes to retinoids, which makes it an interesting therapeutic target. DGAT1 inhibitors are currently at various stages of preclinical and clinical trials, mostly related to metabolic diseases. Interestingly, in recent years, a growing amount of research has shown the influence of DGAT1 on immune cell metabolism and functions, highlighting its important role during infections and tumorigenesis. In this review, we aim to elucidate the potential immunomodulatory effect of DGAT1 in physiological and pathological conditions.
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Affiliation(s)
- Ewa Oleszycka
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Kamila Kwiecień
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Beata Grygier
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Science, Cracow, Poland
| | - Joanna Cichy
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Patrycja Kwiecińska
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland; Laboratory of Stem Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland.
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2
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Seki R, Nagai K, Kobayashi K, Shigeno S, Shirahata T, Kobayashi Y, Ohshiro T, Tomoda H. Celludinone C, a new dihydroisobenzofuran isolated from Talaromyces cellulolyticus BF-0307. J Antibiot (Tokyo) 2025; 78:26-34. [PMID: 39543335 DOI: 10.1038/s41429-024-00785-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/03/2024] [Accepted: 10/17/2024] [Indexed: 11/17/2024]
Abstract
Celludinones A and B, isolated from the fungus Talaromyces cellulolyticus BF-0307, were inhibitors of sterol O-acyltransferase (SOAT). Further searches for their congeners in the culture broth of the fungus by LC/UV and LC/MS analysis resulted in the discovery of four structurally related compounds, including a new dihydroisobenzofuran named celludinone C (1). The structure of 1, including its absolute stereochemistry, was elucidated by 1D/2D NMR and electronic circular dichroism (ECD) spectra. All of these compounds inhibited both SOAT1 and 2, with IC50 values ranging from 8.5 to 30 µM.
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Affiliation(s)
- Reiko Seki
- Medical Research Laboratories, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Kenichiro Nagai
- Medical Research Laboratories, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
| | - Keisuke Kobayashi
- Medical Research Laboratories, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Satoru Shigeno
- Medical Research Laboratories, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Tatsuya Shirahata
- Medical Research Laboratories, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
- Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Yoshinori Kobayashi
- Medical Research Laboratories, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
- Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Taichi Ohshiro
- Medical Research Laboratories, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
| | - Hiroshi Tomoda
- Medical Research Laboratories, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
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3
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Liu Y, Ding F, Deng L, Zhang S, Wu L, Tong H. Discovery of selective ACAT2 antagonist via a combination strategy based on deep docking, pharmacophore modelling, and molecular dynamics simulation. J Enzyme Inhib Med Chem 2024; 39:2403736. [PMID: 39316789 PMCID: PMC11423527 DOI: 10.1080/14756366.2024.2403736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 08/18/2024] [Accepted: 08/29/2024] [Indexed: 09/26/2024] Open
Abstract
Acyl-CoA: cholesterol acyltransferase (ACAT), a pivotal enzyme in the absorption and metabolism of cholesterol, is primarily responsible for intracellular esterification. ACAT inhibition is expected to diminish plasma lipid levels by impeding intestinal cholesterol absorption, thereby preventing the progression of atherosclerotic lesions. A previous study shows that selective inhibition of ACAT2 significantly mitigated hypercholesterolaemia and atherosclerosis in mouse models. Therefore, the need for ACAT2 selective inhibitors becomes particularly urgent. In this study, we established a multilayer virtual screening workflow and subjected biologically evaluated representative compounds to enzyme inhibitory assays. The experimental results indicated that the two compounds, STL565001 (inhibition rate at 25 μM: 75.7 ± 27.8%, selectivity = 6) and STL528213 (inhibition rate at 25 μM: 87.8 ± 12.4%, selectivity = 13), demonstrated robust activity against ACAT2, displaying greater selectivity for ACAT2 than for ACAT1. The molecular mechanisms governing the inhibitory activities of the selected compounds were systematically elucidated using computational approaches. In addition, hotspot residues in ACAT2 that are crucial for ligand binding were successfully identified. In summary, we devised a multilayer screening scheme to expeditiously and efficiently identify compounds with enzyme inhibitory activity, offering novel scaffolds for subsequent drug design centred on ACAT2 targets.
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Affiliation(s)
- Yanfeng Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, China
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, China
| | - Feng Ding
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Liangying Deng
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shuran Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lixing Wu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Huangjin Tong
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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4
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Uchańska A, Morytko A, Kwiecień K, Oleszycka E, Grygier B, Cichy J, Kwiecińska P. Lazy neutrophils - a lack of DGAT1 reduces the chemotactic activity of mouse neutrophils. Inflamm Res 2024; 73:1631-1643. [PMID: 39043892 PMCID: PMC11445369 DOI: 10.1007/s00011-024-01920-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 05/07/2024] [Accepted: 07/11/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Neutrophils are key players in the innate immune system, actively migrating to sites of inflammation in the highly energetic process of chemotaxis. In this study, we focus on the role of acyl-CoA: diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the synthesis of triglycerides, the major form of stored energy, in neutrophil chemotaxis. METHODS AND RESULTS Using a mouse model of psoriasis, we show that DGAT1-deficiency reduces energy-demanding neutrophil infiltration to the site of inflammation, but this inhibition is not caused by decreased glycolysis and reduced ATP production by neutrophils lacking DGAT1. Flow cytometry and immunohistochemistry analysis demonstrate that DGAT1 also does not influence lipid accumulation in lipid droplets during inflammation. Interestingly, as has been shown previously, a lack of DGAT1 leads to an increase in the concentration of retinoic acid, and here, using real-time PCR and publicly-available next-generation RNA sequencing datasets, we show the upregulation of retinoic acid-responsive genes in Dgat1KO neutrophils. Furthermore, supplementation of WT neutrophils with exogenous retinoic acid mimics DGAT1-deficiency in the inhibition of neutrophil chemotaxis in in vitro transwell assay. CONCLUSIONS These results suggest that impaired skin infiltration by neutrophils in Dgat1KO mice is a result of the inhibitory action of an increased concentration of retinoic acid, rather than impaired lipid metabolism in DGAT1-deficient mice.
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Affiliation(s)
- Alicja Uchańska
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
- Selvita S.A, Cracow, Poland
| | - Agnieszka Morytko
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Kamila Kwiecień
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Ewa Oleszycka
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Beata Grygier
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
- Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Science, Cracow, Poland
| | - Joanna Cichy
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Patrycja Kwiecińska
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland.
- Laboratory of Stem Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland.
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Lee J, De La Torre AL, Rawlinson FL, Ness DB, Lewis LD, Hickey WF, Chang CCY, Chang TY. Characterization of Stealth Liposome-Based Nanoparticles Encapsulating the ACAT1/SOAT1 Inhibitor F26: Efficacy and Toxicity Studies In Vitro and in Wild-Type Mice. Int J Mol Sci 2024; 25:9151. [PMID: 39273099 PMCID: PMC11394700 DOI: 10.3390/ijms25179151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 08/19/2024] [Accepted: 08/21/2024] [Indexed: 09/15/2024] Open
Abstract
Cholesterol homeostasis is pivotal for cellular function. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), also abbreviated as SOAT1, is an enzyme responsible for catalyzing the storage of excess cholesterol to cholesteryl esters. ACAT1 is an emerging target to treat diverse diseases including atherosclerosis, cancer, and neurodegenerative diseases. F12511 is a high-affinity ACAT1 inhibitor. Previously, we developed a stealth liposome-based nanoparticle to encapsulate F12511 to enhance its delivery to the brain and showed its efficacy in treating a mouse model for Alzheimer's disease (AD). In this study, we introduce F26, a close derivative of F12511 metabolite in rats. F26 was encapsulated in the same DSPE-PEG2000/phosphatidylcholine (PC) liposome-based nanoparticle system. We employed various in vitro and in vivo methodologies to assess F26's efficacy and toxicity compared to F12511. The results demonstrate that F26 is more effective and durable than F12511 in inhibiting ACAT1, in both mouse embryonic fibroblasts (MEFs), and in multiple mouse tissues including the brain tissues, without exhibiting any overt systemic or neurotoxic effects. This study demonstrates the superior pharmacokinetic and safety profile of F26 in wild-type mice, and suggests its therapeutic potential against various neurodegenerative diseases including AD.
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Affiliation(s)
- Junghoon Lee
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; (J.L.)
| | - Adrianna L. De La Torre
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; (J.L.)
| | - Felix L. Rawlinson
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; (J.L.)
| | - Dylan B. Ness
- Clinical Pharmacology Shared Resource, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA
| | - Lionel D. Lewis
- Clinical Pharmacology Shared Resource, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA
| | - William F. Hickey
- Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA
| | - Catherine C. Y. Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; (J.L.)
| | - Ta Yuan Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; (J.L.)
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Jian HY, Liang ZC, Wen H, Zhang Z, Zeng PH. Shi-pi-xiao-ji formula suppresses hepatocellular carcinoma by reducing cellular stiffness through upregulation of acetyl-coA acetyltransferase 1. World J Gastrointest Oncol 2024; 16:2727-2741. [PMID: 38994152 PMCID: PMC11236261 DOI: 10.4251/wjgo.v16.i6.2727] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 03/14/2024] [Accepted: 04/23/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Previous studies have shown that the Shi-pi-xiao-ji (SPXJ) herbal decoction formula is effective in suppressing hepatocellular carcinoma (HCC), but the underlying mechanisms are not known. Therefore, this study investigated whether the antitumor effects of the SPXJ formula in treating HCC were mediated by acetyl-coA acetyltransferase 1 (ACAT1)-regulated cellular stiffness. Through a series of experiments, we concluded that SPXJ inhibits the progression of HCC by upregulating the expression level of ACAT1, lowering the level of cholesterol in the cell membrane, and altering the cellular stiffness, which provides a new idea for the research of traditional Chinese medicine against HCC. AIM To investigate the anti-tumor effects of the SPXJ formula on the malignant progression of HCC. METHODS HCC cells were cultured in vitro with SPXJ-containing serum prepared by injecting SPXJ formula into wild-type mice. The apoptotic rate and proliferative, invasive, and migratory abilities of control and SPXJ-treated HCC cells were compared. Atomic force microscopy was used to determine the cell surface morphology and the Young's modulus values of the control and SPXJ-treated HCC cells. Plasma membrane cholesterol levels in HCC cells were detected using the Amplex Red cholesterol detection kit. ACAT1 protein levels were estimated using western blotting. RESULTS Compared with the vehicle group, SPXJ serum considerably reduced proliferation of HCC cells, increased stiffness and apoptosis of HCC cells, inhibited migration and invasion of HCC cells, decreased plasma membrane cholesterol levels, and upregulated ACAT1 protein levels. However, treatment of HCC cells with the water-soluble cholesterol promoted proliferation, migration, and invasion of HCC cells as well as decreased cell stiffness and plasma membrane cholesterol levels, but did not alter the apoptotic rate and ACAT1 protein expression levels compared with the vehicle control. CONCLUSION SPXJ formula inhibited proliferation, invasion, and migration of HCC cells by decreasing plasma membrane cholesterol levels and altering cellular stiffness through upregulation of ACAT1 protein expression.
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Affiliation(s)
- Hui-Ying Jian
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zi-Cheng Liang
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Huan Wen
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
| | - Zhen Zhang
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
| | - Pu-Hua Zeng
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
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7
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Jian HY, Liang ZC, Wen H, Zhang Z, Zeng PH. Shi-pi-xiao-ji formula suppresses hepatocellular carcinoma by reducing cellular stiffness through upregulation of acetyl-coA acetyltransferase 1. World J Gastrointest Oncol 2024; 16:2715-2729. [DOI: 10.4251/wjgo.v16.i6.2715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 03/14/2024] [Accepted: 04/23/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Previous studies have shown that the Shi-pi-xiao-ji (SPXJ) herbal decoction formula is effective in suppressing hepatocellular carcinoma (HCC), but the underlying mechanisms are not known. Therefore, this study investigated whether the antitumor effects of the SPXJ formula in treating HCC were mediated by acetyl-coA acetyltransferase 1 (ACAT1)-regulated cellular stiffness. Through a series of experiments, we concluded that SPXJ inhibits the progression of HCC by upregulating the expression level of ACAT1, lowering the level of cholesterol in the cell membrane, and altering the cellular stiffness, which provides a new idea for the research of traditional Chinese medicine against HCC.
AIM To investigate the anti-tumor effects of the SPXJ formula on the malignant progression of HCC.
METHODS HCC cells were cultured in vitro with SPXJ-containing serum prepared by injecting SPXJ formula into wild-type mice. The apoptotic rate and proliferative, invasive, and migratory abilities of control and SPXJ-treated HCC cells were compared. Atomic force microscopy was used to determine the cell surface morphology and the Young’s modulus values of the control and SPXJ-treated HCC cells. Plasma membrane cholesterol levels in HCC cells were detected using the Amplex Red cholesterol detection kit. ACAT1 protein levels were estimated using western blotting.
RESULTS Compared with the vehicle group, SPXJ serum considerably reduced proliferation of HCC cells, increased stiffness and apoptosis of HCC cells, inhibited migration and invasion of HCC cells, decreased plasma membrane cholesterol levels, and upregulated ACAT1 protein levels. However, treatment of HCC cells with the water-soluble cholesterol promoted proliferation, migration, and invasion of HCC cells as well as decreased cell stiffness and plasma membrane cholesterol levels, but did not alter the apoptotic rate and ACAT1 protein expression levels compared with the vehicle control.
CONCLUSION SPXJ formula inhibited proliferation, invasion, and migration of HCC cells by decreasing plasma membrane cholesterol levels and altering cellular stiffness through upregulation of ACAT1 protein expression.
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Affiliation(s)
- Hui-Ying Jian
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Zi-Cheng Liang
- Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Huan Wen
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
| | - Zhen Zhang
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
| | - Pu-Hua Zeng
- Hunan Provincial Hospital of Integrated Traditional Chinese and Western, Cancer Research Institute of Hunan Academy of Traditional Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha 410006, Hunan Province, China
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8
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Greco S, Campigotto M, D’Amuri A, Fabbri N, Passaro A. Dyslipidemia, Cholangitis and Fatty Liver Disease: The Close Underexplored Relationship: A Narrative Review. J Clin Med 2024; 13:2714. [PMID: 38731243 PMCID: PMC11084647 DOI: 10.3390/jcm13092714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 04/25/2024] [Accepted: 04/30/2024] [Indexed: 05/13/2024] Open
Abstract
In assessing individual cardiovascular risk, dyslipidemia is known for emerging as a pivotal factor significantly contributing to major cardiovascular events. However, dyslipidemic patients frequently present with concurrent medical conditions, each with varying frequencies of occurrence; cholangitis, whether acute or chronic, and hepatic steatosis, along with associated conditions, are strongly associated with specific forms of dyslipidemia, and these associations are reasonably well elucidated. Conversely, evidence linking biliary disease to hepatic steatosis is comparatively scant. This narrative review aims to bridge this gap in knowledge concerning the interplay between dyslipidemia, cholangitis, and hepatic steatosis. By addressing this gap, clinicians can better identify patients at heightened risk of future major cardiovascular events, facilitating more targeted interventions and management strategies. The review delves into the intricate relationships between dyslipidemia and these hepatic and biliary clinical conditions, shedding light on potential mechanisms underlying their associations. Understanding these complex interactions is crucial for optimizing cardiovascular risk assessment as well and devising tailored treatment approaches for patients with dyslipidemia and associated hepatic disorders. Moreover, elucidating these connections empowers clinicians with the knowledge needed to navigate the multifaceted landscape of cardiovascular risk assessment and management effectively. By exploring the intricate relationships between dyslipidemia, cholangitis, and hepatic steatosis (without forgetting the possible clinical consequences of hepatic steatosis itself), this review not only contributes to the existing body of knowledge but also offers insights into potential avenues for further research and clinical practice. Thus, it serves as a valuable resource for healthcare professionals striving to enhance patient care and outcomes in the context of cardiovascular disease and associated hepatic conditions.
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Affiliation(s)
- Salvatore Greco
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, FE, Italy;
- Department of Internal Medicine, Ospedale del Delta, Via Valle Oppio 2, 44023 Lagosanto, FE, Italy
| | - Michele Campigotto
- Gastroenterology and Digestive Endoscopy Unit, ASUGI, Cattinara University Hospital, Strada di Fiume 447, 34149 Trieste, TS, Italy;
| | - Andrea D’Amuri
- General Medicine Unit, Medical Department, ASST Mantova, Ospedale Carlo Poma, Strada Lago Paiolo 10, 46100 Mantova, MN, Italy;
| | - Nicolò Fabbri
- Department of General Surgery, Ospedale del Delta, Via Valle Oppio 2, 44023 Lagosanto, FE, Italy;
| | - Angelina Passaro
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, FE, Italy;
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9
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Wei M, Yi P, Huang B, Naz S, Ge C, Shu-Chien AC, Wang Z, Wu X. Insights into sequence characteristics and evolutionary history of DGATs in arthropods. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2024; 49:101195. [PMID: 38266530 DOI: 10.1016/j.cbd.2024.101195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 01/08/2024] [Accepted: 01/16/2024] [Indexed: 01/26/2024]
Abstract
Triacylglycerol (TAG) is crucial in animal energy storage and membrane biogenesis. The conversion of diacylglycerol (DAG) to triacylglycerol (TAG) is catalyzed by diacylglycerol acyltransferase enzymes (DGATs), which are encoded by genes belonging to two distinct gene families. Although arthropods are known to possess DGATs activities and utilize the glycerol-3-phosphate pathway and MAG pathway for TAG biosynthesis, the sequence characterization and evolutionary history of DGATs in arthropods remains unclear. This study aimed to comparatively evaluate genomic analyses of DGATs in 13 arthropod species and 14 outgroup species. We found that arthropods lack SOAT2 genes within the DGAT1 family, while DGAT2, MOGAT3, AWAT1, and AWAT2 were absent from in DGAT2 family. Gene structure and phylogenetic analyses revealed that DGAT1 and DGAT2 genes come from different gene families. The expression patterns of these genes were further analyzed in crustaceans, demonstrating the importance of DGAT1 in TAG biosynthesis. Additionally, we identified the DGAT1 gene in Swimming crab (P. trituberculatus) undergoes a mutually exclusive alternative splicing event in the molt stages. Our newly determined DGAT inventory data provide a more complete scenario and insights into the evolutionary dynamics and functional diversification of DGATs in arthropods.
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Affiliation(s)
- Maolei Wei
- Centre for Research on Fish Nutrition and Environmental Ecology of the Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, China; College of Biological and Environmental Sciences, Zhejiang Wanli University, Ningbo 315100, China
| | - Peng Yi
- Centre for Research on Fish Nutrition and Environmental Ecology of the Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, China
| | - Baoyou Huang
- Institute of Animal Sex and Development, Zhejiang Wanli University, Ningbo 315100, China; College of Biological and Environmental Sciences, Zhejiang Wanli University, Ningbo 315100, China
| | - Saira Naz
- Centre for Research on Fish Nutrition and Environmental Ecology of the Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, China
| | - Chutian Ge
- Institute of Animal Sex and Development, Zhejiang Wanli University, Ningbo 315100, China; College of Biological and Environmental Sciences, Zhejiang Wanli University, Ningbo 315100, China
| | - Alexander Chong Shu-Chien
- School of Biological Sciences, University Sains Malaysia, Minden, 11800 Penang, Malaysia; Center for Chemical Biology, University Sains Malaysia, 11900 Bayan Lepas, Penang, Malaysia
| | - Zongji Wang
- Institute of Animal Sex and Development, Zhejiang Wanli University, Ningbo 315100, China; College of Biological and Environmental Sciences, Zhejiang Wanli University, Ningbo 315100, China.
| | - Xugan Wu
- Centre for Research on Fish Nutrition and Environmental Ecology of the Ministry of Agriculture, Shanghai Ocean University, Shanghai 201306, China; National Demonstration Centre for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China.
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10
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Xu X, Wilkerson A, Li G, Butovich IA, Zuo YY. Comparative Biophysical Study of Meibomian Lipids of Wild Type and Soat1-Null Mice: Implications to Meibomian Gland Dysfunction and Dry Eye Disease. Invest Ophthalmol Vis Sci 2023; 64:20. [PMID: 37585190 PMCID: PMC10434715 DOI: 10.1167/iovs.64.11.20] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 07/28/2023] [Indexed: 08/17/2023] Open
Abstract
Purpose The biophysical roles of Meibomian lipids (MLs) played in health and meibomian gland dysfunction (MGD) are still unclear. The purpose of this research is to establish the composition-structure-functional correlations of the ML film (MLF) using Soat1-null mice and comprehensive in vitro biophysical simulations. Methods MLs were extracted from tarsal plates of wild type (WT) and Soat1 knockout (KO) mice. The chemical composition of ML samples was characterized using liquid chromatography - mass spectrometry. Comprehensive biophysical studies of the MLFs, including their dynamic surface activity, interfacial rheology, evaporation resistance, and ultrastructure and topography, were performed with a novel experimental methodology called the constrained drop surfactometry. Results Soat1 inactivation caused multiple alternations in the ML profile. Compared to their WT siblings, the MLs of KO mice were completely devoid of cholesteryl esters (CEs) longer than C18 to C20, but contained 7 times more free cholesterol (Chl). Biophysical assays consistently suggested that the KO-MLF became stiffer than that of WT mice, revealed by reduced film compressibility, increased elastic modulus, and decreased loss tangent, thus causing more energy loss per blinking cycle of the MLF. Moreover, the KO mice showed thinning of their MLF, and reduced evaporation resistance. Conclusions These findings delineated the composition-structure-functional correlations of the MLF and suggested a potential biophysical function of long-chain CEs in optimizing the surface activity, interfacial rheology, and evaporation resistance of the MLF. This study may provide novel implications to pathophysiological and translational understanding of MGD and dry eye disease.
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Affiliation(s)
- Xiaojie Xu
- Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu, Hawaii, United States
| | - Amber Wilkerson
- Department of Ophthalmology and Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, United States
| | - Guangle Li
- Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu, Hawaii, United States
| | - Igor A. Butovich
- Department of Ophthalmology and Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, United States
| | - Yi Y. Zuo
- Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu, Hawaii, United States
- Department of Pediatrics, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States
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11
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De La Torre AL, Huynh TN, Chang CCY, Pooler DB, Ness DB, Lewis LD, Pannem S, Feng Y, Samkoe KS, Hickey WF, Chang TY. Stealth Liposomes Encapsulating a Potent ACAT1/SOAT1 Inhibitor F12511: Pharmacokinetic, Biodistribution, and Toxicity Studies in Wild-Type Mice and Efficacy Studies in Triple Transgenic Alzheimer's Disease Mice. Int J Mol Sci 2023; 24:11013. [PMID: 37446191 PMCID: PMC10341764 DOI: 10.3390/ijms241311013] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/22/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Cholesterol is essential for cellular function and is stored as cholesteryl esters (CEs). CEs biosynthesis is catalyzed by the enzymes acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), with ACAT1 being the primary isoenzyme in most cells in humans. In Alzheimer's Disease, CEs accumulate in vulnerable brain regions. Therefore, ACATs may be promising targets for treating AD. F12511 is a high-affinity ACAT1 inhibitor that has passed phase 1 safety tests for antiatherosclerosis. Previously, we developed a nanoparticle system to encapsulate a large concentration of F12511 into a stealth liposome (DSPE-PEG2000 with phosphatidylcholine). Here, we injected the nanoparticle encapsulated F12511 (nanoparticle F) intravenously (IV) in wild-type mice and performed an HPLC/MS/MS analysis and ACAT enzyme activity measurement. The results demonstrated that F12511 was present within the mouse brain after a single IV but did not overaccumulate in the brain or other tissues after repeated IVs. A histological examination showed that F12511 did not cause overt neurological or systemic toxicity. We then showed that a 2-week IV delivery of nanoparticle F to aging 3xTg AD mice ameliorated amyloidopathy, reduced hyperphosphorylated tau and nonphosphorylated tau, and reduced neuroinflammation. This work lays the foundation for nanoparticle F to be used as a possible therapy for AD and other neurodegenerative diseases.
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Affiliation(s)
- Adrianna L. De La Torre
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; (A.L.D.L.T.)
| | - Thao N. Huynh
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; (A.L.D.L.T.)
| | - Catherine C. Y. Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; (A.L.D.L.T.)
| | - Darcy B. Pooler
- Clinical Pharmacology Shared Resource, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA
| | - Dylan B. Ness
- Clinical Pharmacology Shared Resource, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA
| | - Lionel D. Lewis
- Clinical Pharmacology Shared Resource, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA
| | - Sanjana Pannem
- Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA; (S.P.); (Y.F.)
| | - Yichen Feng
- Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA; (S.P.); (Y.F.)
| | - Kimberley S. Samkoe
- Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA; (S.P.); (Y.F.)
| | - William F. Hickey
- Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA;
| | - Ta Yuan Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; (A.L.D.L.T.)
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12
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Pierce MR, Hougland JL. A rising tide lifts all MBOATs: recent progress in structural and functional understanding of membrane bound O-acyltransferases. Front Physiol 2023; 14:1167873. [PMID: 37250116 PMCID: PMC10213974 DOI: 10.3389/fphys.2023.1167873] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 04/19/2023] [Indexed: 05/31/2023] Open
Abstract
Acylation modifications play a central role in biological and physiological processes. Across a range of biomolecules from phospholipids to triglycerides to proteins, introduction of a hydrophobic acyl chain can dramatically alter the biological function and cellular localization of these substrates. Amongst the enzymes catalyzing these modifications, the membrane bound O-acyltransferase (MBOAT) family occupies an intriguing position as the combined substrate selectivities of the various family members span all three classes of these biomolecules. MBOAT-dependent substrates are linked to a wide range of health conditions including metabolic disease, cancer, and neurodegenerative disease. Like many integral membrane proteins, these enzymes have presented challenges to investigation due to their intractability to solubilization and purification. However, over the last several years new solubilization approaches coupled with computational modeling, crystallography, and cryoelectron microscopy have brought an explosion of structural information for multiple MBOAT family members. These studies enable comparison of MBOAT structure and function across members catalyzing modifications of all three substrate classes, revealing both conserved features amongst all MBOATs and distinct architectural features that correlate with different acylation substrates ranging from lipids to proteins. We discuss the methods that led to this renaissance of MBOAT structural investigations, our new understanding of MBOAT structure and implications for catalytic function, and the potential impact of these studies for development of new therapeutics targeting MBOAT-dependent physiological processes.
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Affiliation(s)
- Mariah R. Pierce
- Department of Chemistry, Syracuse University, Syracuse, NY, United States
| | - James L. Hougland
- Department of Chemistry, Syracuse University, Syracuse, NY, United States
- Department of Biology, Syracuse University, Syracuse, NY, United States
- BioInspired Syracuse, Syracuse University, Syracuse, NY, United States
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13
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Farese RV, Walther TC. Glycerolipid Synthesis and Lipid Droplet Formation in the Endoplasmic Reticulum. Cold Spring Harb Perspect Biol 2023; 15:a041246. [PMID: 36096640 PMCID: PMC10153804 DOI: 10.1101/cshperspect.a041246] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
More than 60 years ago, Eugene Kennedy and coworkers elucidated the endoplasmic reticulum (ER)-based pathways of glycerolipid synthesis, including the synthesis of phospholipids and triacylglycerols (TGs). The reactions of the Kennedy pathway were identified by studying the conversion of lipid intermediates and the isolation of biochemical enzymatic activities, but the molecular basis for most of these reactions was unknown. With recent progress in the cell biology, biochemistry, and structural biology in this area, we have a much more mechanistic understanding of this pathway and its reactions. In this review, we provide an overview of molecular aspects of glycerolipid synthesis, focusing on recent insights into the synthesis of TGs. Further, we go beyond the Kennedy pathway to describe the mechanisms for storage of TG in cytosolic lipid droplets and discuss how overwhelming these pathways leads to ER stress and cellular toxicity, as seen in diseases linked to lipid overload and obesity.
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Affiliation(s)
- Robert V Farese
- Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
- Center for Causes and Prevention of Cardiovascular Disease (CAP-CVD), Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA
| | - Tobias C Walther
- Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
- Center for Causes and Prevention of Cardiovascular Disease (CAP-CVD), Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA
- Howard Hughes Medical Institute Boston, Boston, Massachusetts 02115, USA
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14
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Zhao Y, Dong Q, Geng Y, Ma C, Shao Q. Dynamic Regulation of Lipid Droplet Biogenesis in Plant Cells and Proteins Involved in the Process. Int J Mol Sci 2023; 24:ijms24087476. [PMID: 37108639 PMCID: PMC10138601 DOI: 10.3390/ijms24087476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Lipid droplets (LDs) are ubiquitous, dynamic organelles found in almost all organisms, including animals, protists, plants and prokaryotes. The cell biology of LDs, especially biogenesis, has attracted increasing attention in recent decades because of their important role in cellular lipid metabolism and other newly identified processes. Emerging evidence suggests that LD biogenesis is a highly coordinated and stepwise process in animals and yeasts, occurring at specific sites of the endoplasmic reticulum (ER) that are defined by both evolutionarily conserved and organism- and cell type-specific LD lipids and proteins. In plants, understanding of the mechanistic details of LD formation is elusive as many questions remain. In some ways LD biogenesis differs between plants and animals. Several homologous proteins involved in the regulation of animal LD formation in plants have been identified. We try to describe how these proteins are synthesized, transported to the ER and specifically targeted to LD, and how these proteins participate in the regulation of LD biogenesis. Here, we review current work on the molecular processes that control LD formation in plant cells and highlight the proteins that govern this process, hoping to provide useful clues for future research.
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Affiliation(s)
- Yiwu Zhao
- Shandong Provincial Key Laboratory of Plant Stress, College of Life Sciences, Shandong Normal University, Jinan 250358, China
| | - Qingdi Dong
- Shandong Provincial Key Laboratory of Plant Stress, College of Life Sciences, Shandong Normal University, Jinan 250358, China
| | - Yuhu Geng
- Shandong Provincial Key Laboratory of Plant Stress, College of Life Sciences, Shandong Normal University, Jinan 250358, China
| | - Changle Ma
- Shandong Provincial Key Laboratory of Plant Stress, College of Life Sciences, Shandong Normal University, Jinan 250358, China
| | - Qun Shao
- Shandong Provincial Key Laboratory of Plant Stress, College of Life Sciences, Shandong Normal University, Jinan 250358, China
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15
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Li H, Huynh TN, Duong MT, Gow JG, Chang CCY, Chang TY. ACAT1/SOAT1 Blockade Suppresses LPS-Mediated Neuroinflammation by Modulating the Fate of Toll-like Receptor 4 in Microglia. Int J Mol Sci 2023; 24:5616. [PMID: 36982689 PMCID: PMC10053317 DOI: 10.3390/ijms24065616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/08/2023] [Accepted: 03/08/2023] [Indexed: 03/17/2023] Open
Abstract
Cholesterol is stored as cholesteryl esters by the enzymes acyl-CoA:cholesterol acyltransferases/sterol O:acyltransferases (ACATs/SOATs). ACAT1 blockade (A1B) ameliorates the pro-inflammatory responses of macrophages to lipopolysaccharides (LPS) and cholesterol loading. However, the mediators involved in transmitting the effects of A1B in immune cells is unknown. Microglial Acat1/Soat1 expression is elevated in many neurodegenerative diseases and in acute neuroinflammation. We evaluated LPS-induced neuroinflammation experiments in control vs. myeloid-specific Acat1/Soat1 knockout mice. We also evaluated LPS-induced neuroinflammation in microglial N9 cells with and without pre-treatment with K-604, a selective ACAT1 inhibitor. Biochemical and microscopy assays were used to monitor the fate of Toll-Like Receptor 4 (TLR4), the receptor at the plasma membrane and the endosomal membrane that mediates pro-inflammatory signaling cascades. In the hippocampus and cortex, results revealed that Acat1/Soat1 inactivation in myeloid cell lineage markedly attenuated LPS-induced activation of pro-inflammatory response genes. Studies in microglial N9 cells showed that pre-incubation with K-604 significantly reduced the LPS-induced pro-inflammatory responses. Further studies showed that K-604 decreased the total TLR4 protein content by increasing TLR4 endocytosis, thus enhancing the trafficking of TLR4 to the lysosomes for degradation. We concluded that A1B alters the intracellular fate of TLR4 and suppresses its pro-inflammatory signaling cascade in response to LPS.
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Affiliation(s)
- Haibo Li
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Thao N. Huynh
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Michael Tran Duong
- Department of Bioengineering, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - James G. Gow
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Catherine C. Y. Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Ta Yuan Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
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16
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Bhattacharjee P, Rutland N, Iyer MR. Targeting Sterol O-Acyltransferase/Acyl-CoA:Cholesterol Acyltransferase (ACAT): A Perspective on Small-Molecule Inhibitors and Their Therapeutic Potential. J Med Chem 2022; 65:16062-16098. [PMID: 36473091 DOI: 10.1021/acs.jmedchem.2c01265] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Sterol O-acyltransferase (SOAT) is a membrane-bound enzyme that aids the esterification of cholesterol and fatty acids to cholesterol esters. SOAT has been studied extensively as a potential drug target, since its inhibition can serve as an alternative to statin therapy. Two SOAT isozymes that have discrete functions in the human body, namely, SOAT1 and SOAT2, have been characterized. Over three decades of research has focused on candidate SOAT1 inhibitors with unsatisfactory results in clinical trials. Recent research has focused on targeting SOAT2 selectively. In this perspective, we summarize the literature covering various SOAT inhibitory agents and discuss the design, structural requirements, and mode of action of SOAT inhibitors.
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Affiliation(s)
- Pinaki Bhattacharjee
- Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States
| | - Nicholas Rutland
- Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States
| | - Malliga R Iyer
- Section on Medicinal Chemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rockville, Maryland 20852, United States
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17
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Moorey AR, Besra GS. The role of triacylglycerols and repurposing DGAT1 inhibitors for the treatment of Mycobacterium tuberculosis. Cell Surf 2022; 8:100083. [PMID: 36277080 PMCID: PMC9578982 DOI: 10.1016/j.tcsw.2022.100083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 10/13/2022] [Accepted: 10/13/2022] [Indexed: 11/09/2022] Open
Abstract
Latent tuberculosis poses a significant threat to global health through the incubation of undiagnosed infections within the community, and through its tolerance to antibiotics. This Special Features article explores the mechanisms by which the dormant Mycobacterium tuberculosis pathogen can store energy in the form of lipid inclusion bodies and triacylglycerols, which may be key in the development of novel therapeutics to treat TB.
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18
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Kou Y, Geng F, Guo D. Lipid Metabolism in Glioblastoma: From De Novo Synthesis to Storage. Biomedicines 2022; 10:1943. [PMID: 36009491 PMCID: PMC9405736 DOI: 10.3390/biomedicines10081943] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/01/2022] [Accepted: 08/06/2022] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma (GBM) is the most lethal primary brain tumor. With limited therapeutic options, novel therapies are desperately needed. Recent studies have shown that GBM acquires large amounts of lipids for rapid growth through activation of sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor that regulates fatty acid and cholesterol synthesis, and cholesterol uptake. Interestingly, GBM cells divert substantial quantities of lipids into lipid droplets (LDs), a specific storage organelle for neutral lipids, to prevent lipotoxicity by increasing the expression of diacylglycerol acyltransferase 1 (DGAT1) and sterol-O-acyltransferase 1 (SOAT1), which convert excess fatty acids and cholesterol to triacylglycerol and cholesteryl esters, respectively. In this review, we will summarize recent progress on our understanding of lipid metabolism regulation in GBM to promote tumor growth and discuss novel strategies to specifically induce lipotoxicity to tumor cells through disrupting lipid storage, a promising new avenue for treating GBM.
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Affiliation(s)
- Yongjun Kou
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, College of Medicine at The Ohio State University, Columbus, OH 43012, USA
| | - Feng Geng
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, College of Medicine at The Ohio State University, Columbus, OH 43012, USA
| | - Deliang Guo
- Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, College of Medicine at The Ohio State University, Columbus, OH 43012, USA
- Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA
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19
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De La Torre AL, Smith C, Granger J, Anderson FL, Harned TC, Havrda MC, Chang CCY, Chang TY. Facile method to incorporate high-affinity ACAT/SOAT1 inhibitor F12511 into stealth liposome-based nanoparticle and demonstration of its efficacy in blocking cholesteryl ester biosynthesis without overt toxicity in neuronal cell culture. J Neurosci Methods 2022; 367:109437. [PMID: 34890698 PMCID: PMC8775100 DOI: 10.1016/j.jneumeth.2021.109437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 11/18/2021] [Accepted: 12/05/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been considered as potential therapeutic agents to treat several diseases, including Alzheimer's disease, atherosclerosis, and cancer. While many ACAT inhibitors are readily available, methods to encapsulate them as nanoparticles have not been reported. NEW METHOD We report a simple method to encapsulate ACAT inhibitors, using the potent hydrophobic ACAT inhibitor F12511 as an example. By mixing DSPE-PEG2000, egg phosphatidylcholine (PC), and F12511 in ethanol, followed by drying, resuspension and sonication in buffer, we show that F12511 can be encapsulated as stealth liposomes at high concentration. RESULTS We successfully incorporated F12511 into nanoparticles and found that increasing PC in the nanoparticles markedly increased the amount of F12511 incorporated in stealth liposomes. The nanoparticles containing F12511 (Nanoparticle F) exhibit average size of approximately 200 nm and are stable at 4 ºC for at least 6 months. Nanoparticle F is very effective at inhibiting ACAT in human and mouse neuronal and microglial cell lines. Toxicity tests using mouse primary neuronal cells show that F12511 alone or Nanoparticle F added at concentrations from 2 to 10 µM for 24-, 48-, and 72-hours produces minimal, if any, toxicity. COMPARISON WITH EXISTING METHOD(S) Unlike existing methods, the current method is simple, cost effective, and can be expanded to produce tagged liposomes to increase specificity of delivery. This also offers opportunity to embrace water soluble agent(s) within the aqueous compartment of the nanoparticles for potential combinatorial therapy. CONCLUSIONS This method shows promise for delivery of hydrophobic ACAT inhibitors at high concentration in vivo.
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Affiliation(s)
- Adrianna L. De La Torre
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Caleb Smith
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Joseph Granger
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Faith L. Anderson
- Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Taylor C. Harned
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Matthew C. Havrda
- Department of Molecular and Systems Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Catherine C. Y. Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Ta-Yuan Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
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20
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Chang TY, Chang CCY, Harned TC, De La Torre AL, Lee J, Huynh TN, Gow JG. Blocking cholesterol storage to treat Alzheimer's disease. EXPLORATION OF NEUROPROTECTIVE THERAPY 2021; 1:173-184. [PMID: 35199105 PMCID: PMC8863366 DOI: 10.37349/ent.2021.00014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/07/2021] [Indexed: 12/11/2022]
Abstract
Cholesterol serves as an essential lipid molecule in various membrane organelles of mammalian cells. The metabolites of cholesterol also play important functions. Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), also named as sterol O-acyltransferase 1, is a membrane-bound enzyme residing at the endoplasmic reticulum (ER). It converts cholesterol to cholesteryl esters (CEs) for storage, and is expressed in all cells. CEs cannot partition in membranes; they can only coalesce as cytosolic lipid droplets. Excess CEs are found in the vulnerable region of the brains of patients with late-onset Alzheimer's disease (AD), and in cell and mouse models for AD. Reducing CE contents by genetic inactivation of ACAT1, or by pharmacological inhibition of ACAT is shown to reduce amyloidopathy and other hallmarks for AD. To account for the various beneficial actions of the ACAT1 blockade (A1B), a working hypothesis is proposed here: the increase in CE contents observed in the AD brain is caused by damages of cholesterol-rich lipid rafts that are known to occur in neurons affected by AD. These damages cause cholesterol to release from lipid rafts and move to the ER where it will be converted to CEs by ACAT1. In addition, the increase in CE contents may also be caused by overloading with cholesterol-rich substances, or through activation of ACAT1 gene expression by various proinflammatory agents. Both scenarios may occur in microglia of the chronically inflamed brain. A1B ameliorates AD by diverting the cholesterol pool destined for CE biosynthesis such that it can be utilized more efficiently to repair membrane damage in various organelles, and to exert regulatory actions more effectively to defend against AD. To test the validity of the A1B hypothesis in cell culture and in vivo, the current status of various anti-ACAT1 agents that could be further developed is briefly discussed.
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Affiliation(s)
- Ta Yuan Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Catherine C. Y. Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Taylor C. Harned
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Adrianna L. De La Torre
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Junghoon Lee
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Thao N. Huynh
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - James G. Gow
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
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21
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Long T, Liu Y, Li X. Molecular structures of human ACAT2 disclose mechanism for selective inhibition. Structure 2021; 29:1410-1418.e4. [PMID: 34520735 PMCID: PMC8642284 DOI: 10.1016/j.str.2021.07.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/13/2021] [Accepted: 07/20/2021] [Indexed: 12/14/2022]
Abstract
Endoplasmic reticulum-localized acyl-CoA:cholesterol acyltransferases (ACAT), including ACAT1 and ACAT2, convert cholesterol to cholesteryl esters that become incorporated into lipoproteins or stored in cytosolic lipid droplets. Selective inhibition of ACAT2 has been shown to considerably attenuate hypercholesterolemia and atherosclerosis in mice. Here, we report cryogenic electron microscopy structures of human ACAT2 bound to its specific inhibitor pyripyropene A or the general ACAT inhibitor nevanimibe. Structural analysis reveals that ACAT2 has a topology in membranes similar to that of ACAT1. A catalytic core with an entry site occupied by a cholesterol molecule and another site for allosteric activation of ACAT2 is observed in these structures. Enzymatic assays show that mutations within sites of cholesterol entry or allosteric activation attenuate ACAT2 activity in vitro. Together, these results reveal mechanisms for ACAT2-mediated esterification of cholesterol, providing a blueprint to design new ACAT2 inhibitors for use in the prevention of cardiovascular disease.
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Affiliation(s)
- Tao Long
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yang Liu
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xiaochun Li
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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22
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Zhu T, Wang Z, Zou T, Xu L, Zhang S, Chen Y, Chen C, Zhang W, Wang S, Ding Q, Xu G. SOAT1 Promotes Gastric Cancer Lymph Node Metastasis Through Lipid Synthesis. Front Pharmacol 2021; 12:769647. [PMID: 34790132 PMCID: PMC8591064 DOI: 10.3389/fphar.2021.769647] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/19/2021] [Indexed: 12/25/2022] Open
Abstract
Emerging evidences demonstrate that metabolic reprogramming is a hallmark of malignancies, including gastric cancer (GC). Abnormal expression of metabolic rate-limiting enzymes, as the executive medium of energy metabolism, drives the occurrence and development of cancer. However, a comprehensive model of metabolic rate-limiting enzymes associated with the development and progression of GC remains unclear. In this research, we identified a rate-limiting enzyme, sterol O-acyltransferase 1 (SOAT1), was highly expressed in cancerous tissues, which was associated with advanced tumor stage and lymph node metastasis, leading to the poor prognosis of GC. It was shown that knockdown of SOAT1 or pharmacological inhibition of SOAT1 by avasimibe could suppress GC cell proliferation, cholesterol ester synthesis, and lymphangiogenesis. However, overexpression of SOAT1 promoted these biological processes. Mechanistically, SOAT1 regulated the expression of cholesterol metabolism genes SREBP1 and SREBP2, which could induce lymphangiogenesis via increasing the expression of VEGF-C. In conclusion, our results indicated that SOAT1 promotes gastric cancer lymph node metastasis through lipid synthesis, which suggested that it may be a promising prognostic biomarker for guiding clinical management and treatment decisions.
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Affiliation(s)
- Tingting Zhu
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhangding Wang
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Tianhui Zou
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai, China
| | - Lei Xu
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Shu Zhang
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Yali Chen
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Chen Chen
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Weijie Zhang
- Department of Thyroid and Breast Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Shouyu Wang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.,Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.,Center for Public Health Research, Medical School of Nanjing University, Nanjing, China
| | - Qingqing Ding
- Department of Gerontology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guifang Xu
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
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23
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Govatati S, Pichavaram P, Mani AM, Kumar R, Sharma D, Dienel A, Meena S, Puchowicz MA, Park EA, Rao GN. Novel role of xanthine oxidase-dependent H 2O 2 production in 12/15-lipoxygenase-mediated de novo lipogenesis, triglyceride biosynthesis and weight gain. Redox Biol 2021; 47:102163. [PMID: 34655995 PMCID: PMC8577505 DOI: 10.1016/j.redox.2021.102163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/07/2021] [Accepted: 10/07/2021] [Indexed: 11/16/2022] Open
Abstract
12/15-lipoxygenase (12/15-LOX) plays an essential role in oxidative conversion of polyunsaturated fatty acids into various bioactive lipid molecules. Although 12/15-LOX's role in the pathophysiology of various human diseases has been well studied, its role in weight gain is controversial and poorly clarified. Here, we demonstrated the role of 12/15-LOX in high-fat diet (HFD)-induced weight gain in a mouse model. We found that 12/15-LOX mediates HFD-induced de novo lipogenesis (DNL), triglyceride (TG) biosynthesis and the transport of TGs from the liver to adipose tissue leading to white adipose tissue (WAT) expansion and weight gain via xanthine oxidase (XO)-dependent production of H2O2. 12/15-LOX deficiency leads to cullin2-mediated ubiquitination and degradation of XO, thereby suppressing H2O2 production, DNL and TG biosynthesis resulting in reduced WAT expansion and weight gain. These findings infer that manipulation of 12/15-LOX metabolism may manifest a potential therapeutic target for weight gain and obesity.
12/15-LOX-12(S)-HETE axis via activation of CREB-Egr1 enhances TG biosynthesis. 12/15-LOX-12(S)-HETE axis via activation of SREBP1c triggers DNL. H2O2 mediates 12/15-LOX-12(S)-HETE axis-induced DNL and TG biosynthesis. 12/15-LOX via TG biosynthesis leads to WAT expansion and body weight gain. Downstream to 12/15-LOX, H2O2-mediates WAT expansion and body weight gain.
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Affiliation(s)
- Suresh Govatati
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Prahalathan Pichavaram
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Arul M Mani
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Raj Kumar
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Deepti Sharma
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Ari Dienel
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Sunita Meena
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Michelle A Puchowicz
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Edwards A Park
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Gadiparthi N Rao
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
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24
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Fujiwara Y, Okada S, Uryu K, Maru I, Komohara Y. The extract of Ilex kudingcha inhibits atherosclerosis in apoE-deficient mice by suppressing cholesterol accumulation in macrophages. Biosci Biotechnol Biochem 2021; 85:2177-2184. [PMID: 34369980 DOI: 10.1093/bbb/zbab140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/27/2021] [Indexed: 11/13/2022]
Abstract
It was previously reported that oleanolic acid and ursolic acid, triterpenoid compounds occurring in Ilex kudingcha, ameliorate hyperlipidemia and atherosclerosis in apoE-deficient mice. In the present study, we investigated whether I. kudingcha extract exerts similar inhibitory effects on cholesterol accumulation in human monocyte-derived macrophages (HMDMs) and atherogenesis in apoE-deficient mice. I. kudingcha extract significantly inhibited cholesterol ester (CE) accumulation induced by acetylated LDL (acetyl-LDL) in HMDMs; however, it generated no effect on cell viability in HMDMs. I. kudingcha extract also suppressed CE accumulation in acyl-CoA:cholesterol acyl-transferase (ACAT)-overexpressing Chinese hamster ovary (CHO) cells, thereby indicating that it inhibits ACAT activity. Furthermore, the oral administration of I. kudingcha extract to apoE-deficient mice significantly decreased the levels of serum cholesterol, triglyceride, sLOX-1, as well as the regions of atherosclerotic lesions in the mice. Our study reveals crucial new-found evidence that I. kudingcha extract significantly inhibits ACAT activity and suppresses atherogenesis.
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Affiliation(s)
- Yukio Fujiwara
- Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | | | | | | | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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25
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Horn CL, Morales AL, Savard C, Farrell GC, Ioannou GN. Role of Cholesterol-Associated Steatohepatitis in the Development of NASH. Hepatol Commun 2021; 6:12-35. [PMID: 34558856 PMCID: PMC8710790 DOI: 10.1002/hep4.1801] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 07/08/2021] [Accepted: 07/14/2021] [Indexed: 12/11/2022] Open
Abstract
The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand the mechanisms causing progression of hepatic steatosis to fibrosing steatohepatitis and cirrhosis in a small proportion of patients with NAFLD. Accumulating evidence suggests that lipotoxicity mediated by hepatic free cholesterol (FC) overload is a mechanistic driver for necroinflammation and fibrosis, characteristic of nonalcoholic steatohepatitis (NASH), in many animal models and also in some patients with NASH. Diet, lifestyle, obesity, key genetic polymorphisms, and hyperinsulinemia secondary to insulin resistance are pivotal drivers leading to aberrant cholesterol signaling, which leads to accumulation of FC within hepatocytes. FC overload in hepatocytes can lead to ER stress, mitochondrial dysfunction, development of toxic oxysterols, and cholesterol crystallization in lipid droplets, which in turn lead to hepatocyte apoptosis, necrosis, or pyroptosis. Activation of Kupffer cells and hepatic stellate cells by hepatocyte signaling and cholesterol loading contributes to this inflammation and leads to hepatic fibrosis. Cholesterol accumulation in hepatocytes can be readily prevented or reversed by statins. Observational studies suggest that use of statins in NASH not only decreases the substantially increased cardiovascular risk, but may ameliorate liver pathology. Conclusion: Hepatic FC loading may result in cholesterol-associated steatohepatitis and play an important role in the development and progression of NASH. Statins appear to provide significant benefit in preventing progression to NASH and NASH-cirrhosis. Randomized controlled trials are needed to demonstrate whether statins or statin/ezetimibe combination can effectively reverse steatohepatitis and liver fibrosis in patients with NASH.
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Affiliation(s)
- Christian L Horn
- Division of Gastroenterology and Hepatology, Department of Medicine, San Antonio Military Medical Center, Fort Sam Houston, TX, USA
| | - Amilcar L Morales
- Division of Gastroenterology and Hepatology, Department of Medicine, San Antonio Military Medical Center, Fort Sam Houston, TX, USA
| | - Christopher Savard
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.,Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA.,Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
| | - Geoffrey C Farrell
- Liver Research Group, ANU Medical School, Australian National University at the Canberra Hospital, Garran, ACT, Australia
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.,Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA.,Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
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26
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Laubach K, Zhang J, Chen X. The p53 Family: A Role in Lipid and Iron Metabolism. Front Cell Dev Biol 2021; 9:715974. [PMID: 34395447 PMCID: PMC8358664 DOI: 10.3389/fcell.2021.715974] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/08/2021] [Indexed: 12/11/2022] Open
Abstract
The p53 family of tumor suppressors, which includes p53, p63, and p73, has a critical role in many biological processes, such as cell cycle arrest, apoptosis, and differentiation. In addition to tumor suppression, the p53 family proteins also participate in development, multiciliogenesis, and fertility, indicating these proteins have diverse roles. In this review, we strive to cover the relevant studies that demonstrate the roles of p53, p63, and p73 in lipid and iron metabolism.
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Affiliation(s)
| | | | - Xinbin Chen
- Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California, Davis, Davis, CA, United States
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27
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Peng Y, Li H, Liu Z, Zhang C, Li K, Gong Y, Geng L, Su J, Guan X, Liu L, Zhou R, Zhao Z, Guo J, Liang Q, Li X. Chromosome-level genome assembly of the Arctic fox (Vulpes lagopus) using PacBio sequencing and Hi-C technology. Mol Ecol Resour 2021; 21:2093-2108. [PMID: 33829635 DOI: 10.1111/1755-0998.13397] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 03/28/2021] [Accepted: 03/30/2021] [Indexed: 10/21/2022]
Abstract
The Arctic fox (Vulpes lagopus) is the only fox species occurring in the Arctic and has adapted to its extreme climatic conditions. Currently, the molecular basis of its adaptation to the extreme climate has not been characterized. Here, we applied PacBio sequencing and chromosome structure capture technique to assemble the first V. lagopus genome assembly, which is assembled into chromosome fragments. The genome assembly has a total length of 2.345 Gb with a contig N50 of 31.848 Mb and a scaffold N50 of 131.537 Mb, consisting of 25 pseudochromosomal scaffolds. The V. lagopus genome had approximately 32.33% repeat sequences. In total, 21,278 protein-coding genes were predicted, of which 99.14% were functionally annotated. Compared with 12 other mammals, V. lagopus was most closely related to V. Vulpes with an estimated divergence time of ~7.1 Ma. The expanded gene families and positively selected genes potentially play roles in the adaptation of V. lagopus to Arctic extreme environment. This high-quality assembled genome will not only promote future studies of genetic diversity and evolution in foxes and other canids but also provide important resources for conservation of Arctic species.
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Affiliation(s)
- Yongdong Peng
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation (Under Planning), College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Hong Li
- Novogene Bioinformatics Institute, Beijing, China
| | - Zhengzhu Liu
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation (Under Planning), College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Chuansheng Zhang
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation (Under Planning), College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Keqiang Li
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation (Under Planning), College of Mathematics and Information Science, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Yuanfang Gong
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation (Under Planning), College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Liying Geng
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation (Under Planning), College of Agronomy and Biotechnology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Jingjing Su
- Hebei Key Laboratory of Applied Chemistry, School of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao, China
| | - Xuemin Guan
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation (Under Planning), College of Agronomy and Biotechnology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Lei Liu
- College of Animal Science and Technology, Shandong Agricultural University, Tai-an, China
| | - Ruihong Zhou
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation (Under Planning), College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Ziya Zhao
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation (Under Planning), College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Jianxu Guo
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation (Under Planning), College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
| | - Qiqi Liang
- Novogene Bioinformatics Institute, Beijing, China
| | - Xianglong Li
- Hebei Key Laboratory of Specialty Animal Germplasm Resources Exploration and Innovation (Under Planning), College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
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28
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Duong MT, Nasrallah IM, Wolk DA, Chang CCY, Chang TY. Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy. Front Aging Neurosci 2021; 13:647990. [PMID: 33841127 PMCID: PMC8026881 DOI: 10.3389/fnagi.2021.647990] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/08/2021] [Indexed: 12/18/2022] Open
Abstract
Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration via acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Risk factors including hypercholesterolemia and hypertension promote intracranial atherosclerotic disease and carotid artery stenosis (CAS), which disrupt cerebral blood flow and trigger ischemic strokes and VCID. Apolipoprotein E (APOE) is a cholesterol and phospholipid carrier present in plasma and various tissues. APOE is implicated in dyslipidemia and Alzheimer disease (AD); however, its connection with VCID is less understood. Few experimental models for VCID exist, so much of the present information has been drawn from clinical studies. Here, we review the literature with a focus on the clinical aspects of atherosclerotic cerebrovascular disease and build a working model for the pathogenesis of VCID. We describe potential intermediate steps in this model, linking cholesterol, atherosclerosis, and APOE with VCID. APOE4 is a minor isoform of APOE that promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. APOE4 disturbs lipid homeostasis in macrophages and smooth muscle cells, thus exacerbating systemic inflammation and promoting atherosclerotic plaque formation. Additionally, APOE4 may contribute to stromal activation of endothelial cells and pericytes that disturb the blood-brain barrier (BBB). These and other risk factors together lead to chronic inflammation, atherosclerosis, VCID, and neurodegeneration. Finally, we discuss potential cholesterol metabolism based approaches for future VCID treatment.
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Affiliation(s)
- Michael Tran Duong
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Ilya M Nasrallah
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - David A Wolk
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | | | - Ta-Yuan Chang
- Geisel School of Medicine, Dartmouth College, Hanover, NH, United States
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29
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Interactions of Lipid Droplets with the Intracellular Transport Machinery. Int J Mol Sci 2021; 22:ijms22052776. [PMID: 33803444 PMCID: PMC7967230 DOI: 10.3390/ijms22052776] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 02/27/2021] [Accepted: 02/27/2021] [Indexed: 12/16/2022] Open
Abstract
Historically, studies of intracellular membrane trafficking have focused on the secretory and endocytic pathways and their major organelles. However, these pathways are also directly implicated in the biogenesis and function of other important intracellular organelles, the best studied of which are peroxisomes and lipid droplets. There is a large recent body of work on these organelles, which have resulted in the introduction of new paradigms regarding the roles of membrane trafficking organelles. In this review, we discuss the roles of membrane trafficking in the life cycle of lipid droplets. This includes the complementary roles of lipid phase separation and proteins in the biogenesis of lipid droplets from endoplasmic reticulum (ER) membranes, and the attachment of mature lipid droplets to membranes by lipidic bridges and by more conventional protein tethers. We also discuss the catabolism of neutral lipids, which in part results from the interaction of lipid droplets with cytosolic molecules, but with important roles for both macroautophagy and microautophagy. Finally, we address their eventual demise, which involves interactions with the autophagocytotic machinery. We pay particular attention to the roles of small GTPases, particularly Rab18, in these processes.
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30
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Butovich IA, Wilkerson A, Yuksel S. Depletion of Cholesteryl Esters Causes Meibomian Gland Dysfunction-Like Symptoms in a Soat1-Null Mouse Model. Int J Mol Sci 2021; 22:1583. [PMID: 33557318 PMCID: PMC7915537 DOI: 10.3390/ijms22041583] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/01/2021] [Accepted: 02/01/2021] [Indexed: 02/08/2023] Open
Abstract
Previous studies on ablation of several key genes of meibogenesis related to fatty acid elongation, omega oxidation, and esterification into wax esters have demonstrated that inactivation of any of them led to predicted changes in the meibum lipid profiles and caused severe abnormalities in the ocular surface and Meibomian gland (MG) physiology and morphology. In this study, we evaluated the effects of Soat1 ablation that were expected to cause depletion of the second largest class of Meibomian lipids (ML)-cholesteryl esters (CE)-in a mouse model. ML of the Soat1-null mice were examined using liquid chromatography high-resolution mass spectrometry and compared with those of Soat1+/- and wild-type mice. Complete suppression of CE biosynthesis and simultaneous accumulation of free cholesterol (Chl) were observed in Soat1-null mice, while Soat1+/- mutants had normal Chl and CE profiles. The total arrest of the CE biosynthesis in response to Soat1 ablation transformed Chl into the dominant lipid in meibum accounting for at least 30% of all ML. The Soat1-null mice had clear manifestations of dry eye and MG dysfunction. Enrichment of meibum with Chl and depletion of CE caused plugging of MG orifices, increased meibum rigidity and melting temperature, and led to a massive accumulation of lipid deposits around the eyes of Soat1-null mice. These findings illustrate the role of Soat1/SOAT1 in the lipid homeostasis and pathophysiology of MG.
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Affiliation(s)
- Igor A. Butovich
- Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9057, USA; (A.W.); (S.Y.)
- The Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390-9057, USA
| | - Amber Wilkerson
- Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9057, USA; (A.W.); (S.Y.)
| | - Seher Yuksel
- Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9057, USA; (A.W.); (S.Y.)
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31
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Sun J, Xu X, Huang X, Ji S, Bian C, Ji H. Nuclear factor-κB subunit p65 is involved in lipopolysaccharide-induced lipid accumulation via regulating DGAT1b in Ctenopharyngodon idellus kidney cells. FISH & SHELLFISH IMMUNOLOGY 2020; 105:71-77. [PMID: 32585360 DOI: 10.1016/j.fsi.2020.05.071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/24/2020] [Accepted: 05/26/2020] [Indexed: 06/11/2023]
Abstract
Lipopolysaccharide (LPS) can promote the accumulation of triglycerides (TGs) in CIK (Ctenopharyngodon idellus kidney) cells, but the underlying mechanism is unclear. In this study, two genes involved TG synthesis, DGAT1a and DGAT1b, were isolated and characterized from grass carp Ctenopharyngodon idella, which encode peptides of 498 and 501 amino acids, respectively. Phylogenetic and synteny analyses indicated that DGAT1a and DGAT1b could have originated from the teleost-specific genome duplication event. Analysis of the exon-intron structures clarified that genomic structures of all DGAT1 proteins are conserved in vertebrates. DGAT1a mRNA was highly expressed in gut, adipose tissue and heart, while DGAT1b mRNA was highly expressed in liver and kidney. After LPS treatment, only expression of DGAT1b was up-regulated and knockdown of DGAT1b reduced the content of TG, suggesting that DGAT1b is involved in LPS-induced lipid accumulation. To explore the mechanism underlying the transcriptional regulation of DGAT1b in response to LPS, we cloned DGAT1b promoter sequence. Its promoter sequence consists of IRF7, RelA (p65) and RelB binding elements. Dual luciferase assay and q-PCR suggested that the promoter of DGAT1b can be activated by the overexpression of p65, but cannot be triggered by IRF7 and RelB. Mutational analysis shows that the potential p65 binding sites may locate in the region -111/-100 bp of the DGAT1b promoter. These results indicated that DGAT1b is the target gene of NF-κB p65. Finally, inhibiting p65 effectively decreased LPS-induced lipid accumulation. Taken together, we demonstrate that NF-κB p65 takes part in the lipid accumulation by regulating DGAT1b-induced TG synthesis in LPS signalling in CIK cells. The finding that NF-κB p65 links LPS signalling and TG synthesis adds to our growing appreciation of the interplay between immunity and lipid metabolism in fish.
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Affiliation(s)
- Jian Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Xinxin Xu
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Xiaocheng Huang
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Shanghong Ji
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Chenchen Bian
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Hong Ji
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China.
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32
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Kobayashi A, Suzuki Y, Sugai S. Specificity of transaminase activities in the prediction of drug-induced hepatotoxicity. J Toxicol Sci 2020; 45:515-537. [PMID: 32879252 DOI: 10.2131/jts.45.515] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The activities of the transaminases (aminotransferases) alanine aminotransferase and aspartate aminotransferase in the blood (serum or plasma) are widely used as sensitive markers of possible tissue damage and, in particular for liver toxicity. On the other hand, an increase in transaminase activities is not always accompanied by findings suggestive of hepatotoxicity. Transaminases are some of the key enzymes in the gluconeogenesis and glycolysis pathways and exist in many organs and tissues which have high activities of the gluconeogenesis and glycolysis. The activities of transaminases are altered not only in the liver but also in other organs by modification of gluconeogenesis by nutritional or hormonal factors and this phenomenon leads to alteration of transaminase activity in the blood. Drugs, which are considered to directly or secondarily modify gluconeogenesis through lowering blood glucose levels or activating lipid metabolism, such as α-glucosidase inhibitors and fibrates, slightly increase transaminase activities in the blood but there is little evidence that the phenomenon is related to drug-induced liver injury (DILI). This type of elevations can be called pharmacology-related elevation. The pharmacology-related elevation of transaminase activities sometimes makes it difficult to assess precisely the potential hepatotoxicity of new investigational drugs. Considering the characteristic of transaminases, concomitant use of new biomarkers more specific to hepatic injury is needed in the assessment of DILI both in non-clinical and clinical studies. In this review, we will discuss the specificity of transaminases to DILI and future perspectives for transaminases in the estimation of risk of DILI.
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Affiliation(s)
- Akio Kobayashi
- Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC
| | - Yusuke Suzuki
- Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC
| | - Shoichiro Sugai
- Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC
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33
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Liu X, Ducasa GM, Mallela SK, Kim JJ, Molina J, Mitrofanova A, Wilbon SS, Ge M, Fontanella A, Pedigo C, Santos JV, Nelson RG, Drexler Y, Contreras G, Al-Ali H, Merscher S, Fornoni A. Sterol-O-acyltransferase-1 has a role in kidney disease associated with diabetes and Alport syndrome. Kidney Int 2020; 98:1275-1285. [PMID: 32739420 DOI: 10.1016/j.kint.2020.06.040] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 06/05/2020] [Accepted: 06/11/2020] [Indexed: 12/25/2022]
Abstract
Defective cholesterol metabolism primarily linked to reduced ATP-binding cassette transporter A1 (ABCA1) expression is closely associated with the pathogenesis and progression of kidney diseases, including diabetic kidney disease and Alport Syndrome. However, whether the accumulation of free or esterified cholesterol contributes to progression in kidney disease remains unclear. Here, we demonstrate that inhibition of sterol-O-acyltransferase-1 (SOAT1), the enzyme at the endoplasmic reticulum that converts free cholesterol to cholesterol esters, which are then stored in lipid droplets, effectively reduced cholesterol ester and lipid droplet formation in human podocytes. Furthermore, we found that inhibition of SOAT1 in podocytes reduced lipotoxicity-mediated podocyte injury in diabetic kidney disease and Alport Syndrome in association with increased ABCA1 expression and ABCA1-mediated cholesterol efflux. In vivo, Soat1 deficient mice did not develop albuminuria or mesangial expansion at 10-12 months of age. However, Soat1 deficiency/inhibition in experimental models of diabetic kidney disease and Alport Syndrome reduced cholesterol ester content in kidney cortices and protected from disease progression. Thus, targeting SOAT1-mediated cholesterol metabolism may represent a new therapeutic strategy to treat kidney disease in patients with diabetic kidney disease and Alport Syndrome, like that suggested for Alzheimer's disease and cancer treatments.
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Affiliation(s)
- Xiaochen Liu
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Gloria Michelle Ducasa
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Shamroop Kumar Mallela
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Jin-Ju Kim
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Judith Molina
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Alla Mitrofanova
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Sydney Symone Wilbon
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Mengyuan Ge
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Antonio Fontanella
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Christopher Pedigo
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Javier Varona Santos
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Robert G Nelson
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA
| | - Yelena Drexler
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Gabriel Contreras
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Hassan Al-Ali
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Sandra Merscher
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
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34
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Oni TE, Biffi G, Baker LA, Hao Y, Tonelli C, Somerville TD, Deschênes A, Belleau P, Hwang CI, Sánchez-Rivera FJ, Cox H, Brosnan E, Doshi A, Lumia RP, Khaledi K, Park Y, Trotman LC, Lowe SW, Krasnitz A, Vakoc CR, Tuveson DA. SOAT1 promotes mevalonate pathway dependency in pancreatic cancer. J Exp Med 2020; 217:151922. [PMID: 32633781 PMCID: PMC7478739 DOI: 10.1084/jem.20192389] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 03/28/2020] [Accepted: 05/12/2020] [Indexed: 12/31/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. Altered metabolism is a cancer vulnerability, and several metabolic pathways have been shown to promote PDAC. However, the changes in cholesterol metabolism and their role during PDAC progression remain largely unknown. Here we used organoid and mouse models to determine the drivers of altered cholesterol metabolism in PDAC and the consequences of its disruption on tumor progression. We identified sterol O-acyltransferase 1 (SOAT1) as a key player in sustaining the mevalonate pathway by converting cholesterol to inert cholesterol esters, thereby preventing the negative feedback elicited by unesterified cholesterol. Genetic targeting of Soat1 impairs cell proliferation in vitro and tumor progression in vivo and reveals a mevalonate pathway dependency in p53 mutant PDAC cells that have undergone p53 loss of heterozygosity (LOH). In contrast, pancreatic organoids lacking p53 mutation and p53 LOH are insensitive to SOAT1 loss, indicating a potential therapeutic window for inhibiting SOAT1 in PDAC.
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Affiliation(s)
- Tobiloba E. Oni
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY
| | - Giulia Biffi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Lindsey A. Baker
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Yuan Hao
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
| | - Claudia Tonelli
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | | | - Astrid Deschênes
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | | | - Chang-il Hwang
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA
| | | | - Hilary Cox
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
| | - Erin Brosnan
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Abhishek Doshi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Rebecca P. Lumia
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Kimia Khaledi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Youngkyu Park
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | | | - Scott W. Lowe
- Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY,Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
| | | | | | - David A. Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Correspondence to David A. Tuveson:
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Nur EAA, Kobayashi K, Amagai A, Ohshiro T, Tomoda H. New Terpendole Congeners, Inhibitors of Sterol O-Acyltransferase, Produced by Volutella citrinella BF-0440. Molecules 2020; 25:molecules25133079. [PMID: 32640743 PMCID: PMC7411735 DOI: 10.3390/molecules25133079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 06/30/2020] [Accepted: 07/03/2020] [Indexed: 11/16/2022] Open
Abstract
New terpendoles N-P (1–3) were isolated along with 8 structurally related known compounds including terpendoles and voluhemins from a culture broth of the fungus Volutella citrinella BF-0440. The structures of 1–3 were elucidated using various spectroscopic experiments including 1D- and 2D-NMR. All compounds 1–3 contained a common indole–diterpene backbone. Compounds 2 and 3 had 7 and 6 consecutive ring systems with an indole ring, respectively, whereas 1 had a unique indolinone plus 4 consecutive ring system. Compounds 2 and 3 inhibited both sterol O-acyltransferase 1 and 2 isozymes, but 1 lost the inhibitory activity. Structure–activity relationships of fungal indole–diterpene compounds are discussed.
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Affiliation(s)
- Elyza Aiman Azizah Nur
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan; (E.A.A.N.); (K.K.); (T.O.)
| | - Keisuke Kobayashi
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan; (E.A.A.N.); (K.K.); (T.O.)
- Medicinal Research Laboratories, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan
| | - Ai Amagai
- Department of Microbial Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan;
| | - Taichi Ohshiro
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan; (E.A.A.N.); (K.K.); (T.O.)
- Department of Microbial Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan;
- ITOCHU Collaborative Research-Molecular Targeted Cancer Treatment for Next Generation, Graduate School of Medicine, Nagoya University, Aichi 466-8550, Japan
| | - Hiroshi Tomoda
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan; (E.A.A.N.); (K.K.); (T.O.)
- Medicinal Research Laboratories, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan
- Department of Microbial Chemistry, School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan;
- Correspondence:
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36
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Ohshiro T, Morita H, Nur EAA, Hosoda K, Uchida R, Tomoda H. Voluhemins, new inhibitors of sterol O-acyltransferase, produced by Volutella citrinella BF-0440. J Antibiot (Tokyo) 2020; 73:748-755. [PMID: 32467602 DOI: 10.1038/s41429-020-0327-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 04/13/2020] [Accepted: 05/07/2020] [Indexed: 11/09/2022]
Abstract
New compounds, designated voluhemins A (1) and B (2), are isolated from the culture broth of the fungal strain Volutella citrinella BF-0440 along with structurally related known NK12838 (3). Spectroscopic data, including 1D and 2D NMR, elucidated their structures. Compounds 1-3 have a common indoline-diterpene core and two additional isoprenyl moieties. Compounds 1 and 3 contain a hemiaminal unit, while 2 is O-methylated 1. Their inhibitory activities toward sterol O-acyltransferase (SOAT) 1 and 2 isozymes in SOAT1- and SOAT2-expressing Chinese hamster ovary (CHO) cells show that 2 selectively inhibits the SOAT2 isozyme.
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Affiliation(s)
- Taichi Ohshiro
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. .,Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. .,Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
| | - Haruka Morita
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Elyza Aiman Azizah Nur
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Kanji Hosoda
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.,Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan
| | - Ryuji Uchida
- Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan
| | - Hiroshi Tomoda
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan. .,Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
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37
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Structure of nevanimibe-bound tetrameric human ACAT1. Nature 2020; 581:339-343. [PMID: 32433613 DOI: 10.1038/s41586-020-2295-8] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Accepted: 03/17/2020] [Indexed: 11/08/2022]
Abstract
Cholesterol is an essential component of mammalian cell membranes, constituting up to 50% of plasma membrane lipids. By contrast, it accounts for only 5% of lipids in the endoplasmic reticulum (ER)1. The ER enzyme sterol O-acyltransferase 1 (also named acyl-coenzyme A:cholesterol acyltransferase, ACAT1) transfers a long-chain fatty acid to cholesterol to form cholesteryl esters that coalesce into cytosolic lipid droplets. Under conditions of cholesterol overload, ACAT1 maintains the low cholesterol concentration of the ER and thereby has an essential role in cholesterol homeostasis2,3. ACAT1 has also been implicated in Alzheimer's disease4, atherosclerosis5 and cancers6. Here we report a cryo-electron microscopy structure of human ACAT1 in complex with nevanimibe7, an inhibitor that is in clinical trials for the treatment of congenital adrenal hyperplasia. The ACAT1 holoenzyme is a tetramer that consists of two homodimers. Each monomer contains nine transmembrane helices (TMs), six of which (TM4-TM9) form a cavity that accommodates nevanimibe and an endogenous acyl-coenzyme A. This cavity also contains a histidine that has previously been identified as essential for catalytic activity8. Our structural data and biochemical analyses provide a physical model to explain the process of cholesterol esterification, as well as details of the interaction between nevanimibe and ACAT1, which may help to accelerate the development of ACAT1 inhibitors to treat related diseases.
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Ichigo Y, Takeshita A, Hibino M, Nakagawa T, Hayakawa T, Patel D, Field CJ, Shimada M. High-Fructose Diet-Induced Hypertriglyceridemia Is Associated With Enhanced Hepatic Expression of ACAT2 in Rats. Physiol Res 2019; 68:1021-1026. [PMID: 31647302 DOI: 10.33549/physiolres.934226] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
High levels of fructose induce hypertriglyceridemia, characterized by excessive levels of triglyceride-rich lipoproteins such as very low-density lipoprotein (VLDL); however, the underlying mechanisms are poorly understood. The aim of this short communication was to examine hepatic changes in the expression of genes related to cholesterol metabolism in rats with hypertriglyceridemia induced by high-fructose or high-glucose diets. Rats were fed a 65 % (w/w) glucose diet or a 65 % (w/w) fructose diet for 12 days. Serum levels of triglycerides, total cholesterol, and VLDL+LDL-cholesterol, hepatic levels of triglycerides and cholesterol, and ACAT2 expression at the gene and protein levels were significantly higher in the fructose diet group compared to the glucose diet group. The hepatic levels of Abcg5/8 were lower in the fructose group than in the glucose group. Serum high-density lipoprotein (HDL)-cholesterol and hepatic expression levels of Hmgcr, Ldlr, Acat1, Mttp, Apob, and Cyp7a1 did not differ significantly between groups. These findings suggest that high-fructose diet-induced hypertriglyceridemia is associated with increased hepatic ACAT2 expression.
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Affiliation(s)
- Y Ichigo
- Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, Yanagido, Gifu, Japan,
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Atorvastatin Improves Hepatic Lipid Metabolism and Protects Renal Damage in Adenine-Induced Chronic Kidney Disease in Sprague-Dawley Rats. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8714363. [PMID: 31828139 PMCID: PMC6885231 DOI: 10.1155/2019/8714363] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 10/09/2019] [Indexed: 11/29/2022]
Abstract
Objective Chronic kidney disease (CKD), including nephrotic syndrome, is a major cause of cardiovascular morbidity and mortality. The literature indicates that CKD is associated with profound lipid disorders largely due to the dysregulation of lipoprotein metabolism which further aggravates the progression of kidney disease. The present study sought to determine the efficacy of atorvastatin treatment on hepatic lipid metabolism and renal tissue damage in CKD rats. Methods Serum, hepatic and faecal lipid contents and the expression and enzyme activity of molecules involved in cholesterol and triglyceride metabolism, along with kidney function, were determined in untreated adenine-induced CKD, atorvastatin-treated CKD (10 mg/kg/day oral for 24 days) and control rats. Key Findings CKD resulted in metabolic dyslipidaemia, renal insufficiency, hepatic lipid accumulation, upregulation of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, acyl-CoA cholesterol acyltransferase-2 (ACAT2) and the downregulation of LDL receptor protein, VLDL receptor, hepatic lipase, lipoprotein lipase (LPL), lecithin–cholesterol acyltransferase (LCAT) and scavenger receptor class B type 1 (SR-B1). CKD also resulted in increased enzymatic activity of HMG-CoA reductase and ACAT2 together with decreased enzyme activity of lipase and LCAT. Atorvastatin therapy attenuated dyslipidaemia, renal insufficiency, reduced hepatic lipids, HMG-CoA reductase and ACAT2 protein abundance and raised LDL receptor and lipase protein expression. Atorvastatin therapy decreased the enzymatic activity of HMG-CoA reductase and increased enzymatic activity of lipase and LCAT. Conclusions Atorvastatin improved hepatic tissue lipid metabolism and renal function in adenine-induced CKD rats.
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40
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Xu Y, Du X, Turner N, Brown AJ, Yang H. Enhanced acyl-CoA:cholesterol acyltransferase activity increases cholesterol levels on the lipid droplet surface and impairs adipocyte function. J Biol Chem 2019; 294:19306-19321. [PMID: 31727739 DOI: 10.1074/jbc.ra119.011160] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/11/2019] [Indexed: 01/21/2023] Open
Abstract
Cholesterol plays essential structural and signaling roles in mammalian cells, but too much cholesterol can cause cytotoxicity. Acyl-CoA:cholesterol acyltransferases 1 and 2 (ACAT1/2) convert cholesterol into its storage form, cholesteryl esters, regulating a key step in cellular cholesterol homeostasis. Adipose tissue can store >50% of whole-body cholesterol. Interestingly, however, almost no ACAT activity is present in adipose tissue, and most adipose cholesterol is stored in its free form. We therefore hypothesized that increased cholesterol esterification may have detrimental effects on adipose tissue function. Here, using several approaches, including protein overexpression, quantitative RT-PCR, immunofluorescence, and various biochemical assays, we found that ACAT1 expression is significantly increased in the adipose tissue of the ob/ob mice. We further demonstrated that ACAT1/2 overexpression partially inhibited the differentiation of 3T3-L1 preadipocytes. In mature adipocytes, increased ACAT activity reduced the size of lipid droplets (LDs) and inhibited lipolysis and insulin signaling. Paradoxically, the amount of free cholesterol increased on the surface of LDs in ACAT1/2-overexpressing adipocytes, accompanied by increased LD localization of caveolin-1. Moreover, cholesterol depletion in adipocytes by treating the cells with cholesterol-deficient media or β-cyclodextrins induced changes in cholesterol distribution that were similar to those caused by ACAT1/2 overexpression. Our results suggest that ACAT1/2 overexpression increases the level of free cholesterol on the LD surface, thereby impeding adipocyte function. These findings provide detailed insights into the role of free cholesterol in LD and adipocyte function and suggest that ACAT inhibitors have potential utility for managing disorders associated with extreme obesity.
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Affiliation(s)
- Yanqing Xu
- School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, New South Wales 2052, Australia
| | - Ximing Du
- School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, New South Wales 2052, Australia
| | - Nigel Turner
- School of Medical Sciences, the University of New South Wales, Sydney, New South Wales 2052, Australia
| | - Andrew J Brown
- School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, New South Wales 2052, Australia
| | - Hongyuan Yang
- School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, New South Wales 2052, Australia
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Shibuya K, Morikawa S, Miyamoto M, Ogawa SI, Tsunenari Y, Urano Y, Noguchi N. Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution. ACS OMEGA 2019; 4:16943-16955. [PMID: 31646241 PMCID: PMC6796924 DOI: 10.1021/acsomega.9b02307] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 09/06/2019] [Indexed: 06/10/2023]
Abstract
An acyl-CoA:cholesterol O-acyltransferase-1 (ACAT-1/SOAT-1) inhibitor, K-604 is a promising drug candidate for the treatment of Alzheimer's disease and glioblastoma; however, it exhibits poor solubility in neutral water and low permeability across the blood-brain barrier. In this study, we report the successful delivery of K-604 to the brain via the intranasal route in mice using a hydroxycarboxylic acid solution. In cerebral tissue, the AUC of K-604 after intranasal administration (10 μL; 108 μg of K-604/mouse) was 772 ng·min/g, whereas that after oral administration (166 μg of K-604/mouse) was 8.9 ng·min/g. Thus, the index of brain-targeting efficiency was 133-fold based on the dose conversion. Even with intranasal administration of K-604 once per day for 7 days, the level of cholesteryl esters markedly decreased from 0.70 to 0.04 μmol/g in the mouse brain. Thus, this application will be a crucial therapeutic solution for ACAT-1 overexpressing diseases in the brain.
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Affiliation(s)
- Kimiyuki Shibuya
- Tokyo
New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
| | - Shigeru Morikawa
- Tokyo
New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
| | - Masayoshi Miyamoto
- Tokyo
New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
| | - Shin-ichiro Ogawa
- Tokyo
New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
| | - Yoshihiko Tsunenari
- Tokyo
New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
| | - Yasuomi Urano
- Department
of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan
| | - Noriko Noguchi
- Department
of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan
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42
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Melton EM, Li H, Benson J, Sohn P, Huang LH, Song BL, Li BL, Chang CCY, Chang TY. Myeloid Acat1/ Soat1 KO attenuates pro-inflammatory responses in macrophages and protects against atherosclerosis in a model of advanced lesions. J Biol Chem 2019; 294:15836-15849. [PMID: 31495784 DOI: 10.1074/jbc.ra119.010564] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/02/2019] [Indexed: 11/06/2022] Open
Abstract
Cholesterol esters are a key ingredient of foamy cells in atherosclerotic lesions; their formation is catalyzed by two enzymes: acyl-CoA:cholesterol acyltransferases (ACATs; also called sterol O-acyltransferases, or SOATs) ACAT1 and ACAT2. ACAT1 is present in all body cells and is the major isoenzyme in macrophages. Whether blocking ACAT1 benefits atherosclerosis has been under debate for more than a decade. Previously, our laboratory developed a myeloid-specific Acat1 knockout (KO) mouse (Acat1 -M/-M), devoid of ACAT1 only in macrophages, microglia, and neutrophils. In previous work using the ApoE KO (ApoE -/-) mouse model for early lesions, Acat1 -M/-M significantly reduced lesion macrophage content and suppressed atherosclerosis progression. In advanced lesions, cholesterol crystals become a prominent feature. Here we evaluated the effects of Acat1 -M/-M in the ApoE KO mouse model for more advanced lesions and found that mice lacking myeloid Acat1 had significantly reduced lesion cholesterol crystal contents. Acat1 -M/-M also significantly reduced lesion size and macrophage content without increasing apoptotic cell death. Cell culture studies showed that inhibiting ACAT1 in macrophages caused cells to produce less proinflammatory responses upon cholesterol loading by acetyl low-density lipoprotein. In advanced lesions, Acat1 -M/-M reduced but did not eliminate foamy cells. In advanced plaques isolated from ApoE -/- mice, immunostainings showed that both ACAT1 and ACAT2 are present. In cell culture, both enzymes are present in macrophages and smooth muscle cells and contribute to cholesterol ester biosynthesis. Overall, our results support the notion that targeting ACAT1 or targeting both ACAT1 and ACAT2 in macrophages is a novel strategy to treat advanced lesions.
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Affiliation(s)
- Elaina M Melton
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755
| | - Haibo Li
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755
| | | | - Paul Sohn
- Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Li-Hao Huang
- Department of Pathology and Immunology, Washington University, St. Louis, Missouri 63130
| | - Bao-Liang Song
- College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Bo-Liang Li
- Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China
| | - Catherine C Y Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755
| | - Ta-Yuan Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755
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Neumann B, Chang CCY, Chang TY. Triton X-100 or octyl glucoside inactivates acyl-CoA:cholesterol acyltransferase 1 by dissociating it from a two-fold dimer to a two-fold monomer. Arch Biochem Biophys 2019; 671:103-110. [PMID: 31251920 DOI: 10.1016/j.abb.2019.06.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 06/12/2019] [Accepted: 06/21/2019] [Indexed: 11/26/2022]
Abstract
Cholesterol is an important lipid molecule and is needed for all mammalian cells. In various cell types, excess cholesterol is stored as cholesteryl esters; acyl-CoA:cholesterol acyltransferase 1 (ACAT1) plays an essential role in this storage process. ACAT1 is located at the endoplasmic reticulum and has nine transmembrane domains (TMDs). It is a member of the membrane-bound O-acyltransferase (MBOAT) family, in which members contain multiple TMDs and participate in a variety of biological functions. When solubilized in the zwitterionic detergent CHAPS, ACAT1 can be purified to homogeneity with full enzyme activity and behaves as a homotetrameric protein. ACAT1 contains two dimerization motifs. The first motif is located near the N-terminus and is not conserved in MBOATs. Deletion of the N-terminal dimerization domain converts ACAT1 to a dimer with full catalytic activity; therefore, ACAT1 is a two-fold dimer. The second dimerization domain, located near the C-terminus, is conserved in MBOATs; however, it was not known whether the C-terminal dimerization domain is required for enzyme activity. Here we show that treating ACAT1 with non-ionic detergent, Triton X-100 or octyl glucoside, causes the enzyme to become a two-fold monomer without any enzymatic activity. Detergent exchange of Triton X-100 with CHAPS restores ACAT1 to a two-fold dimer but fails to restore its enzymatic activity. These results implicate that ACAT1 requires hydrophobic subunit interactions near the C-terminus in order to remain active as a two-fold dimer. Our results also caution the use of Triton X-100 or octyl glucoside to purify other MBOATs.
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Affiliation(s)
- Bryan Neumann
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA
| | - Catherine C Y Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA.
| | - Ta-Yuan Chang
- Department of Biochemistry and Cell Biology, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA.
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44
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Lee J, Ridgway ND. Substrate channeling in the glycerol-3-phosphate pathway regulates the synthesis, storage and secretion of glycerolipids. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1865:158438. [PMID: 30959116 DOI: 10.1016/j.bbalip.2019.03.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/26/2019] [Accepted: 03/27/2019] [Indexed: 01/16/2023]
Abstract
The successive acylation of glycerol-3-phosphate (G3P) by glycerol-3-phosphate acyltransferases and acylglycerol-3-phosphate acyltransferases produces phosphatidic acid (PA), a precursor for CDP-diacylglycerol-dependent phospholipid synthesis. PA is further dephosphorylated by LIPINs to produce diacylglycerol (DG), a substrate for the synthesis of triglyceride (TG) by DG acyltransferases and a precursor for phospholipid synthesis via the CDP-choline and CDP-ethanolamine (Kennedy) pathways. The channeling of fatty acids into TG for storage in lipid droplets and secretion in lipoproteins or phospholipids for membrane biogenesis is dependent on isoform expression, activity and localization of G3P pathway enzymes, as well as dietary and hormonal and tissue-specific factors. Here, we review the mechanisms that control partitioning of substrates into lipid products of the G3P pathway.
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Affiliation(s)
- Jonghwa Lee
- Atlantic Research Center, Depts. of Pediatrics and Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS, Canada
| | - Neale D Ridgway
- Atlantic Research Center, Depts. of Pediatrics and Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS, Canada.
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45
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Ye L, Cao Z, Lai X, Wang W, Guo Z, Yan L, Wang Y, Shi Y, Zhou N. Niacin fine-tunes energy homeostasis through canonical GPR109A signaling. FASEB J 2019; 33:4765-4779. [PMID: 30596513 DOI: 10.1096/fj.201801951r] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The incidence of overweight and obesity has become a global public health problem, constituting a major risk factor for numerous comorbidities. Despite tremendous efforts, effective pharmacological agents for the treatment of obesity are still limited. Here, we showed that in contrast to lactate receptor GPR81, niacin receptor GPR109A-deficient mice had progressive weight gain and hepatic fat accumulation. Using high-fat diet-induced mouse model of obesity, we demonstrated that niacin treatment apparently protected against obesity without affecting food intake in wild-type mice but not in GPR109A-deficient mice. Further investigation showed that niacin treatment led to a remarkable inhibition of hepatic de novo lipogenesis. Additionally, we demonstrated that niacin treatment triggered brown adipose tissue and/or white adipose tissue thermogenic activity via activation of GPR109A. Moreover, we observed that mice exposed to niacin exhibited a dramatic decrease in intestinal absorption of sterols and fatty acids. Taken together, our findings demonstrate that acting on GPR109A, niacin shows the potential to maintain energy homeostasis through multipathways, representing a potential approach to the treatment of obesity, diabetes and cardiovascular disease.-Ye, L., Cao, Z., Lai, X., Wang, W., Guo, Z., Yan, L., Wang, Y., Shi, Y., Zhou, N. Niacin fine-tunes energy homeostasis through canonical GPR109A signaling.
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Affiliation(s)
- Lingyan Ye
- Institute of Biochemistry, College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, China
| | - Zheng Cao
- Institute of Biochemistry, College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, China
| | - Xiangru Lai
- Institute of Biochemistry, College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, China
| | - Weiwei Wang
- Institute of Biochemistry, College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, China
| | - Zhiqiang Guo
- Institute of Biochemistry, College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, China
| | - Lili Yan
- Institute of Biochemistry, College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, China
| | - Yuyan Wang
- Institute of Biochemistry, College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, China
| | - Ying Shi
- Institute of Biochemistry, College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, China
| | - Naiming Zhou
- Institute of Biochemistry, College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, China
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46
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Lee KR, Chae SH, Kim MJ, Chae YJ, Lee MY, Lee CW, Kang JS, Yoon WK, Won YS, Lee K, Moon OS, Kim YK, Kim HC. Determination of Penicillium griseofulvum-oriented pyripyropene A, a selective inhibitor of acyl-coenzyme A:cholesterol acyltransferase 2, in mouse plasma using liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic studies. Biomed Chromatogr 2019; 33:e4388. [PMID: 30238481 DOI: 10.1002/bmc.4388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/06/2018] [Accepted: 09/15/2018] [Indexed: 11/10/2022]
Abstract
In this study, we developed a method for the determination of Penicillium griseofulvum-oriented pyripyropene A (PPPA), a selective inhibitor of acyl-coenzyme A:cholesterol acyltransferase 2, in mouse and human plasma and validated it using liquid chromatography-tandem mass spectrometry. Pyripyropene A (PPPA) and an internal standard, carbamazepine, were separated using a Xterra MS C18 column with a mixture of acetonitrile and 0.1% formic acid as the mobile phase. The ion transitions monitored in positive-ion mode [M + H]+ of multiple-reaction monitoring (MRM) were m/z 148.0 from m/z 584.0 for PPPA and m/z 194.0 from m/z 237.0 for the internal standard. The detector response was specific and linear for PPPA at concentrations within the range from 1 to 5,000 ng/mL. The intra-/inter-day precision and accuracy of the method was acceptable by the criteria for assay validation. The matrix effects of PPPA ranged from 97.6 to 104.2% and from 93.3 to 105.3% in post-preparative mouse and human plasma samples, respectively. PPPA was also stable under various processing and/or handling conditions. Finally, PPPA concentrations in the mouse plasma samples could be measured after intravenous, intraperitoneal, or oral administration of PPPA, suggesting that the assay is useful for pharmacokinetic studies on mice and applicable to human studies.
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Affiliation(s)
- Kyeong-Ryoon Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
| | - Song-Hee Chae
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
| | - Min Ju Kim
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
| | - Yoon-Jee Chae
- CKD Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Myung Yeol Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
| | - Chang Woo Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
| | - Jong Soon Kang
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
| | - Won-Kee Yoon
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
| | - Young-Suk Won
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
| | - Kihoon Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
| | - Og-Sung Moon
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
| | - Young-Kook Kim
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
| | - Hyoung-Chin Kim
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk, South Korea
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Volkmar N, Thezenas ML, Louie SM, Juszkiewicz S, Nomura DK, Hegde RS, Kessler BM, Christianson JC. The ER membrane protein complex promotes biogenesis of sterol-related enzymes maintaining cholesterol homeostasis. J Cell Sci 2019; 132:jcs.223453. [PMID: 30578317 PMCID: PMC6362398 DOI: 10.1242/jcs.223453] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 12/03/2018] [Indexed: 12/24/2022] Open
Abstract
The eukaryotic endoplasmic reticulum (ER) membrane contains essential complexes that oversee protein biogenesis and lipid metabolism, impacting nearly all aspects of cell physiology. The ER membrane protein complex (EMC) is a newly described transmembrane domain (TMD) insertase linked with various phenotypes, but whose clients and cellular responsibilities remain incompletely understood. We report that EMC deficiency limits the cellular boundaries defining cholesterol tolerance, reflected by diminished viability with limiting or excessive extracellular cholesterol. Lipidomic and proteomic analyses revealed defective biogenesis and concomitant loss of the TMD-containing ER-resident enzymes sterol-O-acyltransferase 1 (SOAT1) and squalene synthase (SQS, also known as FDFT1), which serve strategic roles in the adaptation of cells to changes in cholesterol availability. Insertion of the weakly hydrophobic tail-anchor (TA) of SQS into the ER membrane by the EMC ensures sufficient flux through the sterol biosynthetic pathway while biogenesis of polytopic SOAT1 promoted by the EMC provides cells with the ability to store free cholesterol as inert cholesteryl esters. By facilitating insertion of TMDs that permit essential mammalian sterol-regulating enzymes to mature accurately, the EMC is an important biogenic determinant of cellular robustness to fluctuations in cholesterol availability. This article has an associated First Person interview with the first author of the paper. Highlighted Article: The ER membrane protein complex promotes biogenesis of key membrane-bound enzymes responsible for regulation of cholesterol biosynthesis and storage, an important determinant of mammalian cell viability.
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Affiliation(s)
- Norbert Volkmar
- Ludwig Institute for Cancer Research, University of Oxford, ORCRB, Headington, Oxford, OX3 7DQ, UK
| | - Maria-Laetitia Thezenas
- Target Discovery Institute (TDI) Mass Spectrometry Laboratory, Nuffield Department of Medicine, University of Oxford, Headington, Oxford, OX3 7DQ, UK
| | - Sharon M Louie
- Dept. of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California-Berkeley, Berkeley, CA, 94720, USA
| | - Szymon Juszkiewicz
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Daniel K Nomura
- Dept. of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California-Berkeley, Berkeley, CA, 94720, USA
| | - Ramanujan S Hegde
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
| | - Benedikt M Kessler
- Target Discovery Institute (TDI) Mass Spectrometry Laboratory, Nuffield Department of Medicine, University of Oxford, Headington, Oxford, OX3 7DQ, UK
| | - John C Christianson
- Ludwig Institute for Cancer Research, University of Oxford, ORCRB, Headington, Oxford, OX3 7DQ, UK .,Oxford Centre for Translational Myeloma Research, NDORMS, University of Oxford, Botnar Research Centre, Headington, Oxford, OX3 7LD, UK
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48
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Shibuya K, Kawamine K, Ozaki C, Ohgiya T, Edano T, Yoshinaka Y, Tsunenari Y. Discovery of Clinical Candidate 2-(4-(2-((1H-Benzo[d]imidazol-2-yl)thio)ethyl)piperazin-1-yl)-N-(6-methyl-2,4-bis(methylthio)pyridin-3-yl)acetamide Hydrochloride [K-604], an Aqueous-Soluble Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor. J Med Chem 2018; 61:10635-10650. [DOI: 10.1021/acs.jmedchem.8b01256] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Kimiyuki Shibuya
- Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., 2-17-43, Noguchicho,
Higashimurayama, Tokyo 189-0022, Japan
| | - Katsumi Kawamine
- Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., 2-17-43, Noguchicho,
Higashimurayama, Tokyo 189-0022, Japan
| | - Chiyoka Ozaki
- Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., 2-17-43, Noguchicho,
Higashimurayama, Tokyo 189-0022, Japan
| | - Tadaaki Ohgiya
- Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., 2-17-43, Noguchicho,
Higashimurayama, Tokyo 189-0022, Japan
| | - Toshiyuki Edano
- Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., 2-17-43, Noguchicho,
Higashimurayama, Tokyo 189-0022, Japan
| | - Yasunobu Yoshinaka
- Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., 2-17-43, Noguchicho,
Higashimurayama, Tokyo 189-0022, Japan
| | - Yoshihiko Tsunenari
- Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., 2-17-43, Noguchicho,
Higashimurayama, Tokyo 189-0022, Japan
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49
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Ohshiro T, Seki R, Fukuda T, Uchida R, Tomoda H. Celludinones, new inhibitors of sterol O-acyltransferase, produced by Talaromyces cellulolyticus BF-0307. J Antibiot (Tokyo) 2018; 71:1000-1007. [PMID: 30177721 DOI: 10.1038/s41429-018-0097-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 07/26/2018] [Accepted: 08/03/2018] [Indexed: 11/09/2022]
Abstract
New indanones, designated celludinones A ((±)-1) and B (2), were isolated from the culture broth of the fungal strain Talaromyces cellulolyticus BF-0307. The structures of celludinones were elucidated by spectroscopic data, including 1D and 2D NMR. Celludinone A was found to be a mixture of racemic isomers ((±)-1), which were isolated by a chiral column. Compounds (+)-1 and (-)-1 inhibited the sterol O-acyltransferase (SOAT) 1 and 2 isozymes in a cell-based assay using SOAT1- and SOAT2-expressing Chinese hamster ovary (CHO) cells, while 2 selectively inhibited the SOAT2 isozyme.
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Affiliation(s)
- Taichi Ohshiro
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan
- Medicinal Research Laboratories, School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Reiko Seki
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan
| | - Takashi Fukuda
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan
- Department of Fisheries Faculty of Agriculture, and Agricultural Technology and Innovation Research Institute, Kinki University, Nara, Japan
| | - Ryuji Uchida
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan
- Department of Natural Product Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Miyagi, Japan
| | - Hiroshi Tomoda
- Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
- Medicinal Research Laboratories, School of Pharmacy, Kitasato University, Tokyo, Japan.
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50
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Huang LS, Yuen JJ, Trites MJ, Saha A, Epps CT, Hu Y, Kerolle S, Lee SA, Jiang H, Goldberg IJ, Blaner WS, Clugston RD. Dietary Macronutrient Composition Determines the Contribution of DGAT1 to Alcoholic Steatosis. Alcohol Clin Exp Res 2018; 42:2298-2312. [PMID: 30192394 PMCID: PMC6286229 DOI: 10.1111/acer.13881] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 09/02/2018] [Indexed: 01/01/2023]
Abstract
Background The first stage of alcoholic liver disease is hepatic steatosis. While alcohol is known to profoundly impact hepatic lipid metabolism, gaps in our knowledge remain regarding the mechanisms leading to alcohol‐induced hepatic triglyceride (TG) accumulation. As the sole enzymes catalyzing the final step in TG synthesis, diacylglycerol O‐acyltransferase (DGAT) 1 and 2 are potentially important contributors to alcoholic steatosis. Our goal was to study the effects of dietary fat content on alcohol‐induced hepatic TG accumulation, and the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis. Methods These studies were carried out in wild‐type (WT) mice fed alcohol‐containing high‐fat or low‐fat formulations of Lieber‐DeCarli liquid diets, as well as follow‐up studies in Dgat1−/− mice. Results A direct comparison of the low‐fat and high‐fat liquid diet in WT mice revealed surprisingly similar levels of alcoholic steatosis, although there were underlying differences in the pattern of hepatic lipid accumulation and expression of genes involved in hepatic lipid metabolism. Follow‐up studies in Dgat1−/− mice revealed that these animals are protected from alcoholic steatosis when consumed as part of a high‐fat diet, but not a low‐fat diet. Conclusions Dietary macronutrient composition influences the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis, such that in the context of alcohol and a high‐fat diet, DGAT1 predominates.
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Affiliation(s)
- Li-Shin Huang
- Department of Medicine, Columbia University, New York, New York
| | - Jason J Yuen
- Department of Medicine, Columbia University, New York, New York
| | - Michael J Trites
- Department of Physiology, University of Alberta, Edmonton, AB, Canada
| | - Amit Saha
- Department of Medicine, Columbia University, New York, New York
| | - Caleb T Epps
- Department of Medicine, Columbia University, New York, New York
| | - Yungying Hu
- Department of Medicine, New York University Langone Medical Center, New York, New York
| | | | - Seung-Ah Lee
- Department of Medicine, Columbia University, New York, New York
| | - Hongfeng Jiang
- Department of Medicine, Columbia University, New York, New York
| | - Ira J Goldberg
- Department of Medicine, New York University Langone Medical Center, New York, New York
| | | | - Robin D Clugston
- Department of Physiology, University of Alberta, Edmonton, AB, Canada
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